CN111116647B - 一种具有hdac抑制活性的磷酸类化合物及其制备方法与用途 - Google Patents
一种具有hdac抑制活性的磷酸类化合物及其制备方法与用途 Download PDFInfo
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Abstract
一种具有HDAC抑制活性的磷酸类化合物及其制备方法与用途。本发明属于医药技术领域,本发明提供了一种式(I)所示的磷酸类化合物、或其构象异构、或其光学异构体。式I:
Description
技术领域
本发明涉及一种具有HDAC抑制活性的磷酸类化合物及其制备方法与用途。
背景技术
组蛋白去乙酰化酶 (HDAC)是催化去除组蛋白和非组蛋白中赖氨酸残基乙酰基的关键酶,在基因转录、细胞周期进程、细胞凋亡、肿瘤发生等方面具有重要作用。目前,HDAC在多种疾病中,例如肿瘤中均有异常高表达。因此,HDAC靶向治疗有望成为一种有效的治疗方法,HDAC抑制剂有望被发展成为疾病靶向治疗剂。当前已有数百个HDAC抑制剂 (HDACi)被设计合成了,其结构丰富多样,但是多HDACi是Zn2+依赖型,根据其与Zn2+的鳌合类型主要分为四类:第一类,异羟肟酸类,代表药物SAHA(2006年批准上市);第二类,环四肽类,代表药物Romidepsin (2009年批准上市);第三类,苯甲酰胺类,代表抑制剂Chidamide (2014年上市);第四类,脂肪酸类,代表抑制剂为Valproic acid (III期临床试验)等。
在这些抑制剂中,异羟肟酸的HDACi的活性通常要强于其他类型的HDACi。但是,异羟肟酸类HDACi在体内不稳定,容易代谢成有毒的物质;此外,目前大多数的HDACis均是广谱类,被摄取后将广泛的分布在组织中的各个HDAC亚型,由于不同亚型的功能不同,这种缺乏选择性通常会产生不良副作用,如疲劳、血小板减少、恶心/呕吐和心脏毒性等。已经有临床数据表明,SAHA可导致血栓形成神经毒性,FK228存在心脏毒性。这些缺点严格限制了HDACis在临床上的广泛应用。所以,开发出结构新型、高效、低毒的HDACi是迫在眉睫的任务。
发明内容
为了解决上述问题,本发明提供了一种具有HDAC抑制活性的磷酸类化合物,及其制备。
为了实现上述发明目的,本发明采用以下技术方案:
一种结构式如式I的化合物:
式I
其中,R为 H、Me、OMe、F。
本发明的另一目的在于上述化合物或其异构体,在制备HDAC抑制剂类药物中的用途。
所述的HDAC抑制剂类药物是治疗由HDAC活性异常所导致的疾病。
进一步,所述疾病是细胞增殖疾病、自身免疫疾病、炎症、神经变性疾病、病毒性疾病中的任意一种或多种。
更进一步,所述疾病是癌症。
一种抑制组蛋白去乙酰化酶活性的药物组合物,它是以上述化合物或其晶型、药学上可接受的盐、水合物或溶剂合物为活性成分,加上药学上可接受的辅料或辅助性成分制备而成的制剂。
本发明还提供前面结构式I所表示的具有HDAC抑制活性的磷酸类化合物的制备方法,包括以下步骤:
(1) 将苯胺或其衍生物 (对甲苯胺、对甲氧基苯胺、对氟苯胺)、6-庚烯酸溶于二氯甲烷中,然后加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯 (HATU) 和N,N-二异丙基乙胺 (DIEA),室温下搅拌12小时;反应结束之后,加入饱和NaHCO3溶液,二氯甲烷萃取,无水Na2SO4干燥,蒸除二氯甲烷得粗品,经柱层析纯化后得到化合物3a (N-苯基-6-庚烯胺)、3b (N-对甲苯基-6-庚烯胺)、3c (N-对甲氧基苯基-6-庚烯胺)、3d (N-对氟苯基-6-庚烯胺);苯胺或其衍生物、6-庚烯酸、HATU、DIEA的物质的量比为1 : 1.2 : 1.3 :3。
(2) 将化合物3a、3b、3c或3d溶于N,N-二甲基甲酰胺 (DMF)中,加入K2CO3和亚磷酸二苄酯,加热至50 ℃反应2小时;反应结束之后,加入5 %的柠檬酸溶液,乙酸乙酯萃取,无水Na2SO4干燥,蒸除乙酸乙酯得粗 品,经柱层析纯化后得到 (7-氧代-7-苯胺基)庚基磷酸二苄酯化合物4a、4b、4c或4d;化合物3a、3b、3c或3d与K2CO3、亚磷酸二苄酯的物质的量比为1 :2 : 1.6。
(3) 将(7-氧代-7-苯胺基)庚基磷酸二苄酯化合物4a、4b、4c或4d和6 M的HCl进行混合,加热至50℃反应12小时;减压蒸馏除去新生成的甲醇,再加入6 M的HCl,加热至50 ℃反应12小时,减压蒸馏除去新生成的甲醇,加乙酸乙酯萃取,无水Na2SO4干燥,蒸除乙酸乙酯得粗品,经柱层析纯化后得到(7-氧代-7-苯胺基)庚基磷酸化合物5a、5b、5c或5d;(7-氧代-7-苯胺基)庚基磷酸二苄酯化合物、6 M盐酸的物质的量比为1 : 1.7。
上述反应流程如下:
本发明得到的上述一种具有HDAC抑制活性的磷酸类化合物对HDAC酶有较强的抑制活性。
本发明得到的上述一种具有HDAC抑制活性的磷酸类化合物对乳腺癌MCF-7、MDA-MB-231细胞较强的抑制活性,并对正常的乳腺上皮细胞MCF-10A没有毒性。
与现有的技术相比,本发明的有益效果为:
(1)本发明的抑制剂以磷酸为鳌合基团与HDAC酶活性口袋中锌离子结合,不同于传统的异羟肟酸、苯甲酰胺类鳌合基团。因此,磷酸类化合物是一类新型的HDAC抑制剂。
(2)本发明的抑制剂对正常乳腺上皮细胞没有毒性。
(3)本发明的制备方法简单,条件温和,产率高,提供了一种新的药物研发思路,提高了治疗癌症的药物的利用效率和治疗效果,对于实体瘤的抑制具有显著的效果。
具体实施方式
为了使本发明的目的、技术方案和优点更加清楚,下面将对本发明的技术方案进行详细的描述。显然,所描述的实施例仅仅是本发明的一部分实施例,而不是其全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创新性劳动的前提下所得到的所有其它实施方式,都属于本发明保护的范围。
实施例1:(7-氧代-7-苯胺基)庚基磷酸 (5a)的制备
本实施例中(7-氧代-7-苯胺基)庚基磷酸 (5a)的化学结构如下:
本实施例中5a的合成路线如下:
N-苯基-6-庚烯胺 (3a)的合成
将苯胺 (502.9 mg, 5.4 mmol)、6-庚烯酸 (833.1 mg, 6.5 mmol)溶于二氯甲烷中,然后加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯 (HATU, 2.662 g,7.0 mmol) 和N,N-二异丙基乙胺 (DIEA, 2.094 g, 16.2 mmol),室温下搅拌12小时;反应结束之后,加入25 mL饱和NaHCO3溶液,二氯甲烷 (3 × 10 mL)萃取,无水Na2SO4干燥,蒸除二氯甲烷得粗品,经柱层析纯化后得到602.7 mg化合物3a,产率为54.9%。
(7-氧代-7-苯胺基)庚基磷酸二苄酯 (4a)的合成
将 N-苯基-6-庚烯胺化合物3a (406.6 mg, 2.0 mmol)溶于N,N-二甲基甲酰胺(DMF, 10 mL)中,加入K2CO3 (552.8 mg, 4.0 mmol)和亚磷酸二苄酯 (839.2 mg, 3.2mmol),加热至50℃反应2小时;反应结束之后,加入5 %的柠檬酸溶液 (15 mL),乙酸乙酯(3 × 20 mL)萃取,无水Na2SO4干燥,蒸除乙酸乙酯得粗品,经柱层析纯化后得到 452.2 mg化合物4a,产率为48. 6%。
(7-氧代-7-苯胺基)庚基磷酸 (5a)的合成
将(7-氧代-7-苯胺基)庚基磷酸二苄酯4a (558.6 mg, 1.2 mmol)和6 M的HCl (6mL)进行混合,加热至50℃反应12小时;减压蒸馏除去新生成的甲醇,再加入6 M的HCl (6mL),加热至50 ℃反应12小时,减压蒸馏除去新生成的甲醇,加乙酸乙酯萃取,无水Na2SO4干燥,蒸除乙酸乙酯得粗品,经柱层析纯化后得到279 mg (7-氧代-7-苯胺基)庚基磷酸5a,产率为81.5%。1HNMR (400 M, CDCl3) δ7.55 (d, J = 7.6 Hz, 2H), 7.35 (t, J = 8.0 Hz,2H), 7.11-7.18 (m, 1H), 2.40 (t, J = 7.2 Hz, 2H), 1.75-1.83 (m, 4H), 1.61-1.65 (m, 2H), 1.54 (d, J = 6.8 Hz, 4H). 13CNMR (100 M, CDCl3) δ171.27, 137.94,128.97, 124.26, 119.95, 58.65, 40.00, 37.46, 26.31, 25.40, 25.02.
实施例2:[7-氧代-7-(4-甲基苯胺基)]庚基磷酸 (5b)的合成
制备方法如实施例1,其中苯胺用对甲苯胺替代,产物为白色固体,产率为83.4%。1HNMR (400 M, CDCl3) δ7.41 (d, J = 8.8 Hz, 2H), 7.07 (s, 1H), 6.86 (d, J = 8.8Hz, 2H), 3.79 (s, 3H), 2.35 (t, J = 7.2 Hz, 2H), 1.72-1.78 (m, 2H), 1.52 (d,J = 6.8 Hz, 4H) 1.25-1.33 (m, 4H).
实施例3:[7-氧代-7-(4-甲氧基苯胺基)]庚基磷酸 (5c)的合成
制备方法如实施例1,其中苯胺用对甲氧基苯胺替代,产物为白色固体,产率为86.2%。1HNMR (400 M, CDCl3) δ7.39 (d, J = 8.4 Hz, 2H), 7.24 (s, 1H), 7.12 (d, J= 8.0 Hz, 2H), 2.35 (t, J = 7.2 Hz, 2H), 2.30 (s, 3H), 1.71-1.76 (m, 4H),1.51 (d, J = 6.4 Hz, 4H) 1.25-1.28 (m, 2H).
实施例4:[7-氧代-7-(4-氟苯胺基)]庚基磷酸 (5d)的合成
制备方法如实施例1,其中苯胺用对氟苯胺替代,产物为白色固体,产率为81.8%。1HNMR (400 M, CDCl3) δ7.63 (s, 1H), 7.44-7.44 (m, 2H), 7.00 (t, J = 8.8 Hz,2H), 2.36 (t, J = 7.2 Hz, 2H), 2.29 (t, J = 7.6 Hz, 1H), 1.68-1.74 (m, 3H),1.49 (d, J = 6.4 Hz, 3H), 1.24 (t, J = 6.4 Hz, 2H), 1.18 (d, J = 6.0 Hz, 1H).
实施例5:HDAC酶活性测试实验
采用商业购买的HDAC酶检查试剂盒 (BPS Bioscience 公司)进行操作。首先将化合物用100%DMSO溶解,然后用试剂盒中的缓冲液稀释成25、10、5、1、0.5、0.1、0.05、0.01、0.005、0.001 μM的浓度,加入到96孔板中,接着反应孔板中加入15 μL Hela核提取液 (对照组每孔加入15 μL的缓冲液),在室温反应15 min后加入10 μL荧光底物溶液,开始反应,反应中HDACs蛋白的终浓度为6 nM,trypsin终浓度则为0.05 μM,Ac-peptide 终浓度则为8μM,室温避光反应1小时后,用酶标仪测试荧光强度 (发射波长355 nm,吸收波长为460nm),计算抑制率。具体结果见表1。
表1. 本发明合成的代表性目标化合物5a-d的HDACs抑制活性结果 (IC50, nM)
Compounds | IC<sub>50 </sub> |
5a | 169 |
5b | 192 |
5c | 246 |
5d | 295 |
上述实验结果表明:合成的化合对HDACs酶抑制活性均展现出了较强的抑制效果。
实施例6:磷酸类化合物的抗肿瘤活性实验
将乳腺癌MCF-7、MDA-MB-231,乳腺正常上皮细胞MCF-10A在含10%胎牛血清的有酚红DMEM液体培养基中培养。细胞密度至80%~90%时,消化细胞,并用含10%胎牛血清的无酚红DMEM培养基将细胞悬浮液铺至96孔细胞培养板中。待细胞完全贴壁后,弃去原培养液,每孔加入100 μl新鲜的用含10%胎牛血清的DMEM培养基配制的化合物溶液,化合物浓度梯度为:1×10-8 M, 1×10-7 M, 5×10-7 M, 1×10-6 M, 1×10-5 M, 5×10-5M, 1×10-4 M。药物处理培养3天后,取出培养板,每孔加入20 μL 5 mg/mL MTT工作液,置于37 oC、5% CO2培养箱中孵育4小时。之后吸去每孔液体,然后每孔加入100 μL 二甲亚砜(DMSO),放在微量搅拌器上震荡15分钟使结晶物充分溶解。在酶标仪上读板测试每孔的吸光度值(OD),选取490 nm处波长为主波长,630 nm处波长为参照波长。不同药物浓度对肿瘤细胞的生长抑制作用按下式计算:
以抑制率对药物浓度作直线回归分析,用直线方程求算IC50,具体结果见表2。
表2. 本发明合成的代表性目标化合物5a-d的MCF-7、MDA-MB-231和MCF-10A细胞抑制活性结果(IC50, μM)
Compounds | MCF-7 | MDA-MB-231 | MCF-10A |
5a | 6.9 | 5.5 | > 100 |
5b | 7.5 | 6.2 | > 100 |
5c | 10.8 | 9.3 | > 100 |
5d | 14.3 | 7.6 | > 100 |
上述实验结果表明:合成的化合物不仅对荷尔蒙依赖型(MCF-7)乳腺癌,而且对非荷尔蒙依赖型(MDA-MB-231)乳腺癌均显示出了较好的抗乳腺癌活性。化合物5a (IC50 =5.5 μM)对非荷尔蒙依赖型(MDA-MB-231)乳腺癌展现出了最强的抑制活性。
Claims (1)
1.一种具有HDAC抑制活性的磷酸类化合物的制备方法,其特征在于,包括以下步骤:
(1) 将苯胺、对甲苯胺、对甲氧基苯胺或对氟苯胺与6-庚烯酸溶于二氯甲烷中,然后加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯和N,N-二异丙基乙胺,室温下搅拌12小时;反应结束之后,加入饱和NaHCO3溶液,二氯甲烷萃取,无水Na2SO4干燥,蒸除二氯甲烷得粗品,经柱层析纯化后得到化合物3a、3b、3c或3d;苯胺、对甲苯胺、对甲氧基苯胺或对氟苯胺与6-庚烯酸、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯和N,N-二异丙基乙胺的物质的量比为1 : 1.2 : 1.3 : 3;其中化合物3a、3b、3c或3d的结构式如下:
(2) 将化合物3a、3b、3c或3d溶于N,N-二甲基甲酰胺中,加入K2CO3和亚磷酸二苄酯,加热至50℃反应2小时;反应结束之后,加入5 %的柠檬酸溶液,乙酸乙酯萃取,无水Na2SO4干燥,蒸除乙酸乙酯得粗品,经柱层析纯化后得到化合物4a、4b、4c或4d;化合物3a、3b、3c或3d与K2CO3和亚磷酸二苄酯的物质的量比为1 : 2 : 1.6;其中化合物4a、4b、4c或4d的结构式如下:
(3) 将化合物4a、4b、4c或4d和6 M的HCl进行混合,加热至50 ℃反应12小时;减压蒸馏除去新生成的苄醇,加乙酸乙酯萃取,无水Na2SO4干燥,蒸除乙酸乙酯得粗品,经柱层析纯化后得到具有HDAC抑制活性的磷酸类化合物5a、5b、5c或5d;化合物4a、4b、4c或4d与6 M盐酸的物质的量比为1 : 1.7; 化合物5a、5b、5c或5d的结构式如下:
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1699383A (zh) * | 2000-03-08 | 2005-11-23 | 症变治疗公司 | 新的芳基果糖-1,6-二磷酸酶抑制剂 |
CN109705165A (zh) * | 2019-01-28 | 2019-05-03 | 东北林业大学 | 一种高纯度双环膦酸酯的合成及纯化方法 |
-
2019
- 2019-12-02 CN CN201911213773.7A patent/CN111116647B/zh active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1699383A (zh) * | 2000-03-08 | 2005-11-23 | 症变治疗公司 | 新的芳基果糖-1,6-二磷酸酶抑制剂 |
CN109705165A (zh) * | 2019-01-28 | 2019-05-03 | 东北林业大学 | 一种高纯度双环膦酸酯的合成及纯化方法 |
Non-Patent Citations (4)
Title |
---|
"Exploring DOXP-reductoisomerase binding limits using phosphonatedN-aryl andN-heteroarylcarboxamides as DXR inhibitors";Taryn Bodill et al.,;《Bioorganic & Medicinal Chemistry》;20130507;第21卷(第14期);第4332-4341页 * |
"Synthesis and Biological Properties of α-Thymidine 5"-Aryl Phosphonates";M. A. Ivanov et al.,;《RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY》;20131114;第39卷(第6期);第718-727页 * |
"Synthesis and inhibitory activity of acetamidophosphonic acids against metallo-β-lactamases";Yi-Lin Zhang et al.,;《Phosphorus, Sulfur, and Silicon and the Related Elements》;20160825;第192卷(第1期);第1-5页 * |
"Synthetic Fosmidomycin Analogues with Altered Chelating Moieties Do Not Inhibit 1-Deoxy-D-xylulose 5-phosphate Reductoisomerase or Plasmodium falciparum GrowthIn Vitro";R. Chofor et al.,;《Molecules》;20140224;第19卷(第2期);第2571-2587页 * |
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